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1.
Eur J Cancer ; 174: 200-211, 2022 10.
Article in English | MEDLINE | ID: mdl-36044814

ABSTRACT

INTRODUCTION: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. METHODS: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. RESULTS: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. CONCLUSION: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Crizotinib/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/therapeutic use , Protein Kinase Inhibitors/therapeutic use , RNA , Retrospective Studies
2.
Am J Clin Oncol ; 42(11): 845-850, 2019 11.
Article in English | MEDLINE | ID: mdl-31644442

ABSTRACT

OBJECTIVES: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. MATERIALS AND METHODS: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. RESULTS: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. CONCLUSIONS: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Adult , Age Factors , Aged , Biopsy, Fine-Needle , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cohort Studies , Disease-Free Survival , ErbB Receptors/genetics , Female , Humans , Italy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Molecular Targeted Therapy , Mutation/genetics , Neoplasm Invasiveness/pathology , Neoplasm Staging , Prognosis , Retrospective Studies , Risk Assessment , Sex Factors , Survival Analysis , Treatment Outcome
3.
Anticancer Drugs ; 30(7): e0764, 2019 08.
Article in English | MEDLINE | ID: mdl-30950836

ABSTRACT

In the last few years, immunotherapy has become part of everyday clinical practice for the treatment of many solid tumors including metastatic non-small-cell lung cancer. These drugs, however, can yield a specific toxicity profile that consists of immune-related adverse events (irAEs). Hepatotoxicity is one of irAEs and occurs in about 1-3% of cases and may be manifested by the presence of increate levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase) and/or biliary stasis evidence; in these cases, a differential diagnosis with other hepatic diseases must be considered. We present the case of a 73-year-old man who presented with an alteration in liver function during treatment with pembrolizumab (anti-programmed death 1 monoclonal antibody) for a stage IV nonsquamous non-small-cell lung cancer, which was initially mistaken for drug-induced irAEs hepatic toxicity.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug-Related Side Effects and Adverse Reactions/diagnosis , Liver Diseases/diagnosis , Lung Neoplasms/drug therapy , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Diagnosis, Differential , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/pathology , Humans , Liver Diseases/etiology , Liver Diseases/pathology , Lung Neoplasms/pathology , Male , Prognosis
4.
Scientifica (Cairo) ; 2019: 9136249, 2019.
Article in English | MEDLINE | ID: mdl-30838155

ABSTRACT

BACKGROUND: Severe skin rash is listed among important side effects of EGFR tyrosine kinase inhibitors. Polydatin (PD), a glycosylated polyphenol, is endowed with anti-inflammatory activity in human epidermal keratinocytes. OBJECTIVE: This study evaluated the effect of topical application of a moisturizer containing PD to prevent skin rash in patients with mutated non-small cell lung cancer (NSCLC) treated with afatinib. MATERIALS AND METHODS: Eligible NSCLC patients with metastatic disease were treated with first-line afatinib 40 mg/die. One day before starting systemic therapy, all patients received topical administration of a 1.5% PD-based cream b.i.d. every day until the end of afatinib treatment. RESULTS: Out of 34 treated patients, the incidence of skin rash (all grades) was 41.2% and grade 2 rash was 20.6%, and grade 3 rash was not observed in any of the patients. None of the patients discontinued therapy for toxicity. The mean duration of treatment was 6.4 months, calculated from the time treatment was started to the date treatment was stopped. CONCLUSION: The results showed that a PD-based cream can reduce the incidence of grade ≥2 skin toxicities in patients treated with afatinib. Clinical study registration number: Prot. No. 130/CE Lazio 1 Italy.

5.
J Thorac Oncol ; 14(1): 130-134, 2019 01.
Article in English | MEDLINE | ID: mdl-30217489

ABSTRACT

INTRODUCTION: Histologic transformation from NSCLC to SCLC is a mechanism of resistance in EGFR-mutant tumors but is also occasionally observed in nonmutated NSCLC. METHODS: We performed a multicenter retrospective collection of cases presenting between 2005 and 2017. The objectives were to analyze survival data and to define epidemiologic, clinical, treatment and histomolecular characteristics at both the time of diagnosis of NSCLC and of SCLC. RESULTS: Forty-eight EGFR-mutant NSCLC and 13 non-EGFR-mutant cases were registered. Most EGFR-mutant tumors retained the same EGFR mutation after transformation. The median time to SCLC transformation was shorter in the EGFR-mutant group than in non-EFGR mutants (16 months versus 26 months (p = 0.01)). Both tumors were responsive to platinum etoposide regimens (45% partial response for the EGFR-mutant group versus 40% for non-EFGR mutants). The median overall survival rates were 28 months in the EGFR-mutant group versus 37 months in the non-EFGR-mutant group, respectively. After transformation, the median overall survival was 9 months in the non-EGFR-mutant group versus 10 months in the EGFR-mutant group. CONCLUSIONS: Transformation into SCLC seems to occur more quickly in EGFR mutated tumors; however, once the tumor is transformed its survival and response to treatment seems comparable to that of classical SCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Small Cell Lung Carcinoma/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Retrospective Studies , Small Cell Lung Carcinoma/pathology
6.
Clin Respir J ; 12(2): 524-531, 2018 Feb.
Article in English | MEDLINE | ID: mdl-27717235

ABSTRACT

INTRODUCTION: Lipoid pneumonia is a clinical condition that may be initially asymptomatic or confused with an infectious or malignant lung disease. OBJECTIVES: We report four cases of this pathological condition. METHODS: The first case concerned an 85-year old woman with bilateral confluent pulmonary opacities, ground-glass type. Diagnosis was based on the cytology of the bronchoalveolar lavage (BAL) fluid followed by its ultrastructural examination. The second case was a 47-year-old man with an isolated pulmonary nodule, which was surgically removed; the diagnosis of lipoid pneumonia was formulated on the basis of the histological and electron microscopy examination. The third case concerned a 73-year-old woman, with bilateral hypodense areas at the bases of the lungs where FDG PET/CT scan showed an increased uptake. Diagnosis was formulated by BAL cytology and electron microscopy examination. The fourth case was a 69-year-old man, who performed a virtual colonoscopy for diverticulosis putting in evidence a round mass (3 cm in diameter) with two small peripheral nodules, located in the pulmonary left lower lobe. The histopathological examination of transthoracic biopsy confirmed a lipoid pneumonia. RESULTS AND CONCLUSION: In all four cases, it was put in evidence a prolonged use of a nasal decongestant containing mineral oils. In literature, the most cases described are characterized by a subclinical evolution and were presented as ground glass opacities which evolve, in the later phases, in an interstitial involvement or in a peripheral mass, simulating a lung tumour.


Subject(s)
Lung Neoplasms/pathology , Lung/pathology , Nasal Decongestants/adverse effects , Pneumonia, Lipid/chemically induced , Solitary Pulmonary Nodule/pathology , Aged , Aged, 80 and over , Bronchoalveolar Lavage/methods , Colonoscopy/methods , Diverticulosis, Colonic/diagnostic imaging , Diverticulosis, Colonic/pathology , Female , Humans , Lung/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Male , Middle Aged , Mineral Oil/adverse effects , Pneumonia, Lipid/diagnostic imaging , Pneumonia, Lipid/pathology , Pneumonia, Lipid/physiopathology , Positron Emission Tomography Computed Tomography , Solitary Pulmonary Nodule/surgery , Solitary Pulmonary Nodule/ultrastructure , Tomography, X-Ray Computed
7.
J Transl Med ; 15(1): 196, 2017 09 22.
Article in English | MEDLINE | ID: mdl-28938915

ABSTRACT

BACKGROUND: Neurotrophins (NT) belongs to a family of growth factors which promotes neurons survival and differentiation. Increasing evidence show that NT and their receptor are expressed in lung tissues suggesting a possible role in lung health and disease. Here we investigated the expression and functional role of the TrkB/BDNF axis in idiopathic pulmonary fibrotic lung (myo)fibroblasts. METHODS: Lung fibroblast were isolated from IPF patients and characterized for the expression of mesenchymal markers in comparison to normal lung fibroblasts isolated from non-IPF controls. RESULTS: BDNF treatment promoted mesenchymal differentiation and this effect was counteracted by the TrkB inhibitor K252a. In this regard, we showed that K252a treatment was able to control the expression of transcription factors involved in epithelial to mesenchymal transition (EMT). Accordingly, K252a treatment reduced matrix metalloproteinase-9 enzyme activity and E-cadherin expression while increased cytoplasmic ß-catenin expression. CONCLUSIONS: Our results suggest that BDNF/TrkB axis plays a role in EMT promoting the acquisition of (myo)fibroblast cell phenotype in IPF. Targeting BDNF/TrkB seems to represent a viable approach in order to prevent EMT dependent lung fibrosis.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Epithelial-Mesenchymal Transition , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Receptor, trkB/metabolism , Signal Transduction , Biomarkers/metabolism , Carbazoles/pharmacology , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Indole Alkaloids/pharmacology , Lung/pathology , Male , Middle Aged , Signal Transduction/drug effects
8.
Lung India ; 33(1): 72-4, 2016.
Article in English | MEDLINE | ID: mdl-26933312

ABSTRACT

We report two cases of solitary fibrous tumor of the pleura (SFTP). The first appeared in a young, new mother as a large mass in the upper lobe of the left lung that caused compression of lung parenchyma without significant respiratory symptoms but with polyarticular paraneoplastic syndrome; the other was documented by an occasional chest x-ray in a man affected by chronic obstructive pulmonary disease (COPD) as a small peripheral mass 4 years before and no longer controlled. Both patients underwent surgical resection with quick and full recovery. SFTP is a benign, slow growing neoplasm that is mostly localized. It appears in adult or elderly patients often with few symptoms. The computed tomography (CT) of the chest with contrast medium is important in order to see the shape of the mass and relationships with adjacent structures but only histology can provide the diagnosis. Surgery is the best treatment.

9.
J Cell Physiol ; 231(8): 1745-51, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26633752

ABSTRACT

Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease, characterized by persistent airflow limitation not fully reversible. However, a number of patients with COPD respond to bronchodilator agents. Some studies have shown polymorphisms in the b2-adrenergic (ADRb2) and muscarinic M2 and M3 receptors (CHRM) that may participate in the modulation of the receptor responses. This study was designed to investigate the existence and the role of adrenergic and muscarinic receptor polymorphisms and their functional impact in COPD. Eighty-two patients with COPD and 17 healthy smokers were recruited and screened for ADRb2 (T164I and R175R), for CHRM2 (rs1824024) and for CHRM3 (-513C/A and -492C/T). Among the polymorphisms studied our results was not able to demonstrate statistically significant association between the polymorphisms studied and COPD risk. Contrarily, we identified, in our COPD population, a significant association with the CHRM2 (rs1824024) polymorphism and disease severity, with lower lung function test values, frequent exacerbations, and poor response to anti-cholinergic drugs. These results suggest the potential role of receptor polymorphism assessment to discriminate newly COPD phenotypes. J. Cell. Physiol. 231: 1745-1751, 2016. © 2015 Wiley Periodicals, Inc.


Subject(s)
Polymorphism, Single Nucleotide , Pulmonary Disease, Chronic Obstructive/genetics , Receptor, Muscarinic M2/genetics , Aged , Aged, 80 and over , Bronchodilator Agents/therapeutic use , Case-Control Studies , Disease Progression , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Lung/physiopathology , Male , Middle Aged , Muscarinic Antagonists/therapeutic use , Phenotype , Polymerase Chain Reaction , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Receptor, Muscarinic M2/antagonists & inhibitors , Receptor, Muscarinic M3 , Receptors, Adrenergic, beta-2/genetics , Receptors, Muscarinic/genetics , Respiratory Function Tests , Risk Factors , Sequence Analysis, DNA , Severity of Illness Index , Treatment Outcome
10.
J Cell Physiol ; 231(2): 345-56, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26081799

ABSTRACT

The regulatory role of dopamine (DA) in endocrine, cardiovascular and renal functions has been extensively studied and used for clinical purposes. More recently DA has been indicated as a regulatory molecule for immune cells and malignant cell proliferation. We assessed the expression and the functional role DA, DA receptors, and transporters in primary small cell lung cancer (SCLC). By HPLC DA plasma levels were more elevated in SCLC patients in comparison with NSCLC patients and healthy controls. SCLC cell expressed DA D1- and D2-like receptors and membrane and vesicular transporters at protein and mRNA levels. We also investigated the effects of independent D1- or D2-like receptor stimulation on SCLC cell cultures. DA D1 receptor agonist SKF38393 induced the increase of cAMP levels and DARPP-32 protein expression without affecting SCLC growth rate. Cell treatment with the DA D1 receptor antagonist SCH23390 inhibited SKF38393 effects. In contrast, the DA D2 receptor agonist quinpirole (10 µM) counteracted, in a dose and time dependent way, SCLC cell proliferation, it did not affect cAMP levels and decreased phosphorylated AKT that was induced by DA D2 receptor antagonist sulpiride. However, in only one SCLC line, stimulation of DA D2 receptor failed to inhibit cell proliferation in vitro. This effect was associated to the existence of rs6275 and rs6277 polymorphisms in the D2 gene. These results gave more insight into DA control of lung cancer cell behavior and suggested the existence of different SCLC phenotypes.


Subject(s)
Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Receptors, Dopamine/genetics , Receptors, Dopamine/metabolism , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/metabolism , Adenylyl Cyclases/metabolism , Aged , Aged, 80 and over , Cell Line, Tumor , Dopamine/blood , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Female , Humans , Male , Middle Aged , Phosphorylation , Polymorphism, Single Nucleotide , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Receptors, Dopamine D1/genetics , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism
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